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Review Cinnabarinic Acid and Xanthurenic Acid: Two Unorthodox Kynurenine Metabolites That Interact with Metabotropic Glutamate R

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Review Cinnabarinic Acid and Xanthurenic Acid: Two Unorthodox Kynurenine Metabolites That Interact with Metabotropic Glutamate R *Title page Review Cinnabarinic acid and xanthurenic acid: two unorthodox kynurenine metabolites that interact with metabotropic glutamate receptors. Francesco Fazio 1, Luana Lionetto 2, Martina Curto 3, Luisa Iacovelli 4, Caroline S. Copeland 5, Stuart A. Neale6, Valeria Bruno 1,4 , Giuseppe Battaglia 1, Thomas E. Salt 7 and Ferdinando Nicoletti 1,4 . 1I.R.C.C.S. Neuromed, Pozzilli, Italy; 2Advanced Molecular Diagnostic, IDI-IRCCS, Rome, Italy; 3Department of Molecular Medicine, Sant’Andrea Medical Cen ter, Sapienza University, Rome, Italy; 4Department of Physiology and Pharmacology, Sapienza University, Rome, Italy; 5St George's, University of London, UK; 6Neurexpert Ltd, Kemp House, City Road, London, EC1V 2NX, UK; 7UCL Institute of Ophthalmology, London EC1V 9EL, UK. Running head: Cinnabarinic acid, xanthurenic acid, and glutamate receptors Corresponding Author: Francesco Fazio, PhD I.R.C.C.S. Neuromed, Località Camerelle, 86077, Pozzilli (IS), Italy. Tel. 39 0865 915211 Fax +39 0865 927575 Email: [email protected] *Abstract Abstract Cinnabarinic and xanthurenic acids are kynurenine metabolites generated by oxidative dimerization of 3-hydroxyanthranilic acid and transamination of 3-hydroxykynurenine, respectively. Recent evidence suggests that both compounds can affect brain fuction and neurotransmission and interact with metabotropic glutamate (mGlu) receptors. Cinnabarinic acid behaves as an orthosteric agonist of mGlu4 receptors, whereas some of the effects produced by xanthurenic acid in the CNS involve mGlu2 and mGlu3 receptors. Cinnabarinic acid could play an important role in mechanisms of neuroinflammation acting as a linking bridge between the immune system and the CNS. Xanthurenic acid has potential implications in the pathophysiology of schizophrenia and is a promising candidate as a peripheral biomarker of the disorder. The action of cinnabarinic acid and xanthurenic acid may extend beyond the regulation of mGlu receptors and may involve several diverse molecular targets, such as the aryl hydrocarbon receptor for cinnabarinic acid and vesicular glutamate transporters for xanthurenic acid. The growing interest on these two “unorthodox” metabolites of the kynurenine pathway may unravel new aspects in the complex interaction between tryptophan metabolism and brain function, and lead to the discovery of new potential targets for the treatment of neurological and psychiatric disorders. *Manuscript Click here to view linked References Review Cinnabarinic acid and xanthurenic acid: two unorthodox kynurenine metabolites that interact with metabotropic glutamate receptors. Francesco Fazio 1, Luana Lionetto 2, Martina Curto 3, Luisa Iacovelli 4, Caroline S. Copeland 5, Stuart A. Neale6, Valeria Bruno 1,4 , Giuseppe Battaglia 1, Thomas E. Salt 7 and Ferdinando Nicoletti 1,4 . 1I.R.C.C.S. Neuromed, Pozzilli, Italy; 2Advanced Molecular Diagnostic, IDI-IRCCS, Rome, Italy; 3Department of Molecular Medicine, Sant’Andrea Medical Cen ter, Sapienza University, Rome, Italy; 4Department of Physiology and Pharmacology, Sapienza University, Rome, Italy; 5St George's, University of London, UK; 6Neurexpert Ltd, Kemp House, City Road, London, EC1V 2NX, UK; 7UCL Institute of Ophthalmology, London EC1V 9EL, UK. Running head: Cinnabarinic acid, xanthurenic acid, and glutamate receptors Corresponding Author: Francesco Fazio, PhD I.R.C.C.S. Neuromed, Località Camerelle, 86077, Pozzilli (IS), Italy. Tel. 39 0865 915211 Fax +39 0865 927575 Email: [email protected] Abstract Cinnabarinic and xanthurenic acids are kynurenine metabolites generated by oxidative dimerization of 3-hydroxyanthranilic acid and transamination of 3-hydroxykynurenine, respectively. Recent evidence suggests that both compounds can affect brain fuction and neurotransmission and interact with metabotropic glutamate (mGlu) receptors. Cinnabarinic acid behaves as an orthosteric agonist of mGlu4 receptors, whereas some of the effects produced by xanthurenic acid in the CNS involve mGlu2 and mGlu3 receptors. Cinnabarinic acid could play an important role in mechanisms of neuroinflammation acting as a linking bridge between the immune system and the CNS. Xanthurenic acid has potential implications in the pathophysiology of schizophrenia and is a promising candidate as a peripheral biomarker of the disorder. The action of cinnabarinic acid and xanthurenic acid may extend beyond the regulation of mGlu receptors and may involve several diverse molecular targets, such as the aryl hydrocarbon receptor for cinnabarinic acid and vesicular glutamate transporters for xanthurenic acid. The growing interest on these two “unorthodox” metabolites of the kynurenine pathway may unravel new aspects in the complex interaction between tryptophan metabolism and brain function, and lead to the discovery of new potential targets for the treatment of neurological and psychiatric disorders. Key words: cinnabarinic acid - xanthurenic acid - metabotropic glutamate receptors – neuroinflammation - schizophrenia 1. Introduction The kynurenine pathway of tryptophan metabolism generates a series of neuroactive compounds of which quinolinic acid and kynurenic acid gained popularity in neuroscience for their ability to activate and inhibit NMDA receptors, respectively (Stone and Perkins, 1981; de Carvalho et al. 1996; Parsons et al., 1997; Schwarcz et al., 2012). The interest in these two metabolites gave the wrong impression amongst neuroscientsts that the kynurenine pathway was an « inverse L », with the central metabolite, L-kynurenine, giving raise to kynurenic acid, or, alternatively, to a sequential series of metabolites that include 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid. A great emphasis was placed on two key enzymes, kynurenine monooxygenase (KMO) and kynurenine amino transferase, which drive the metabolic fate of L-kynurenine and tip the balance between kynurenic acid and quinolinic acid (reviewed by Schwarcz et al., 2012). Compounds that are generated « horizontally » by 3-hydroxykynurenine and 3-hydroxyanthranilic acid, i.e. xanthurenic acid and cinnabarinic acid, respectively (Fig. 1), have been considered as « by products » of the kynurenine pathway, with little or no interest for the physiology and pathology of the CNS. However, recent findings suggest that cinnabarinic acid and xanthurenic acid are neuroactive compounds, and that their actions modulate, directly or indirectly, metabotropic glutamate (mGlu) receptors. These receptors form a family of eight subtypes, of which the mGlu4 receptor is targeted by cinnabarinic acid, whereas mGlu2 and mGlu3 receptors are involved in the action of xanthurenic acid (see below). mGlu2, mGlu3, and mGlu4 receptors are coupled to Gi/Go proteins and are preferentially localized at presynaptic nerve terminals, where they negatively regulate neurotransmitter release (reviewed by Nicoletti et al., 2011). mGlu4 receptors are also expressed by antigen-presenting cells, and their activation drives T cell differentiation into regulatory T (Treg) cells, thereby restraining autoimmunity and neuroinflammation (Falarino et al., 2010). The interaction with mGlu receptors, as well as other emerging mechanisms (e.g. inhibition of vesicular glutamate transporters by xanthurenic acid and activation of the aryl hydrocarbon - Ah - receptor by cinnabarinic acid) have generated new interest in these two « unorthodox » kynurenine metabolites. Cinnabarinic acid ( 2-amino-3-oxo-3H-phenoxazine-1,9-dicarboxylic acid ), which is responsible for the anitimicrobial activity of the fungus, Pycnoporus cinnabarinus (Eggert et al., 1997), is generated from enzymatic and non-enzymatic oxidation of 3-hydroxyanthranilic acid (Rao, 1966; Ogawa et al., 1983; Christen et al., 1992). Xanthurenic acid is formed by transamination of 3-hydroxykynurenine (Malina and Martin, 1996). In rat and human brain, transamination of 3-hydroxykynurenine into xanthurenic acid is catalyzed by type-2 kynurenine aminotransferase (Sathysaikumar et al., 2014), the same enzyme that converts kynurenine into kynurenic acid (reviewed by Schwarcz et al., 2012). This review will focus on recent findings highlighting a potential role for cinnabarinic acid and xanthurenic acid in CNS physiology and pathology focusing on the possible involvement of mGlu receptors in the mechanism of action of these compounds. 2. Cinnabarinic acid Recent findings led to the identification of two novel receptor targets for cinnabarinic acid: (i) the mGlu4 receptor; and (ii) the aryl hydrocarbon (Ah) receptor. Interestingy, both receptors have been implicated in mechanisms that lie at the core of neuroinflammation, by regulating the bidirectional communication between antigen presenting cells (APCs) and T lymphocytes at the immunological synapse (reviewed by Volpi et al., 2012). In collaboration with the research groups of Jean-Phlippe Pin and Cyrille Goudet (University of Montpellier, France), and Francine Acher (University Renè Descartes, Paris, France) we have found that cinnabarinic acid behaves as a weak orthosteric agonist of mGlu4 receptors, with no activity at other mGlu receptor subtypes (Fazio et al., 2012). mGlu4 receptors are coupled to Gi/o GTP-binding proteins, and are localized on presynaptic terminals where they negatively regulate neurotransmitter release (reviewed by Nicoletti et al., 2011). Selective positive allosteric modulators (PAMs) of mGlu4 receptors are under development for the treatment of Parkins on’s disease (reviewed by Nickols and Conn, 2014; Walker and Conn, 2015),
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